Method of asymmetrically synthesizing optically active compounds using supported phase chiral sulfonated BINAP catalyst

ABSTRACT

The present invention relates to water soluble chiral sulfonated 2,2&#39;-bis(diphenylphosphino)-1,1&#39;-binaphthyl and its use as organometallic catalysts for asymmetric synthesis of optically active compounds. Asymmetric reactions of the present invention include those reactions in which organometallic catalysts are commonly used. Such reactions include, but are not limited to, reduction and isomerization reactions on unsaturated substrates and carbon--carbon bond forming reactions. Examples of such reactions include, but are not limited to, hydrogenation, hydroboration, hydrosilylation, hydride reduction, hydroformylation, alkylation, allylic alkylation, arylation, alkenylation, epoxidation, hydrocyanation, disilylation, cyclization and isomerization reactions. 
     The catalysts of the present invention provide the advantage of functioning in the presence of water without loss in enantioselectivity relative to the nonsulfonated BINAP catalyst in an organic solvent. As a result, the catalysts of the present invention may be employed in water, water miscible solvents, in aqueous-organic two phase solvent systems and in supported aqueous phase catalysts in organic solvents without loss in enantioselectivity. Further, the catalysts of the present invention may also be effectively employed in highly polar solvents such as primary alcohols and ethylene glycol. 
     The present invention also relates to a method for conducting asymmetric reactions on prochiral unsaturated bonds contained within a compound using the water soluble chiral sulfonated 2,2&#39;-bis(diphenylphosphino)-1,1&#39;-binaphthyl organometallic catalysts of the present invention.

The U.S. Government has certain rights in this invention pursuant toGrant No. CTS-9021017 awarded by the National Science Foundation.

This is a divisional of application Ser. No. 08/199,086, filed Feb. 22,1994, now abandoned.

TECHNICAL FIELD

The present invention is generally directed to water-soluble sulfonatedchiral diphenyl phosphine catalysts useful for the asymmetric synthesisof optically active compounds. More specifically, the present inventionrelates to chiral sulfonated BINAP catalysts.

BACKGROUND OF THE INVENTION

The development of effective asymmetric reactions that enable theenantioselective formation of one chiral center over another continuesto be an important area of research. One such asymmetric reactioninvolves the introduction of a chiral center into a molecule through theenantioselective hydrogenation of a prochiral olefin using a transitionmetal catalyst bearing chiral organic ligands. Numerous chiral phosphinecatalysts have been developed to enantioselectivity introduce chiralcenters to prochiral olefins, carbonyls and imines with highenantiomeric excess. One such class of chiral catalysts employs thechiral phosphine ligand 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl(hereinafter referred to as "BINAP". References reportingenantioselective reactions using the BINAP ligand include: Wu, et al.,Tetrahedron Letters(1993) 34:(37) 5927-5930; Wu, et al., TetrahedronLetters (1992) 33:6331-6334; Tani, et al., J. Chem. Soc. Chem. Commun.(1982) 600; Tani, et al., Angew Chem. Int. Ed. Engl. (1985)24(3):217-219; Naruta, et al., Tetrahedron Letters (1987) 28:4553-4556;Hodgson, et al., J. Organomet. Chem. (1987) 325:627630; Hayashi, et al.,J. Am. Chem. Soc. (1988) 110:5579-5581; Hayashi, et al., J. Am. Chem.Soc. (1989) 111:3426-3428; Kollar, et al., J. Molecular Catalysis (1991)67:191-198; Collman, et al., J. Chem. Soc. Chem. Commun. (1993) 428;Murakami, et al., Bull. Chem. Soc. Jpn. (1992) 65:3094-3102; Yamaguchi,et al., Tetrahedron Asymmetry (1991) 2(7): 663-666; Burgess, et al.,Tetrahedron Asymmetry (1991) 2(7): 613-621; Ozawa, et al., TetrahedronLetters (1993) 34(15):2505-2508; Ozawa, et al., Tetrahedron Letters(1992) 33(11):1485-1488; Ozawa, et al., Chemistry Letters (1992)2177-2180; Kagechika, et al., J. Org. Chem. (1991) 56:4093-4094;Sakamoto, et al., Tetrahedron Letters (1992) 33:68456848; Brunner, etal., J. Organometallic Chem. (1993) 456:71-75; Trost, et al., J. Amer.Chem. Soc., (1980) 102:7932-7934; Miyashita, et al., Tetrahedron (1984)40(8):1245-1253; Waldman, et al., "Selectivity in Catalysis," M. E.Davis and S. L. Snib, Eds. ACS Symposium Series 517 (1993); Ozawa, etal., "Selectivity in Catalysis," M. E. Davis and S. L. Snib, Eds. ACSSymposium Series 517 (1993); Chan, et al., "Selectivity in Catalysis,"M. E. Davis and S. L. Snib, Eds. ACS Symposium Series 517 (1993);Dunina, et al., "Homogeneous Catalysis By The Optically Active ComplexesOf Transition Metals And Its Application In The Synthesis Of BioactiveMolecules" J. Org. Chem. USSR (1993) 28:1547-1600, 1913-1971; WO90/15790; WO 92/09552.

second important area of research relates to the development ofwater-soluble organometallic catalysts. Conventionally, catalyticallyactive organometallic complexes have been applied as homogeneouscatalysts in solution in the organic reaction phase. Difficultiesassociated with recovery of the homogeneous catalysts from the reactantsand products diminish the utility of these homogeneous catalysts,especially when the cost of the catalyst is high or where there is theneed to isolate the reaction products in high purity.

One mode in which water soluble organometallic catalysts have been usedis in two phase systems comprising an aqueous phase and a waterimmiscible phase (e.g. ethyl acetate-water). Separation of theorganometallic catalyst from organic reactants and products is greatlysimplified due to the insolubility of the catalyst in the waterimmiscible phase. However, in some instances, the utility of the twophase system has been limited by a lack of substrate and/or reactantsolubility in the aqueous phase and by the limited interfacial areabetween the two phases. For example, in the case of hydrogenationreactions, the solubility of dihydrogen in water at 25° C. and 1 atm is8.53×10⁻⁴ M, over four times smaller than the solubility of dihydrogenin ethanol (38.2×10⁻⁴ M).

Supported aqueous phase organometallic catalysts (SAP) have beendeveloped to overcome some of the shortcomings associated with two phasereaction systems. In particular, SAP catalysts greatly enhance theinterfacial area between the aqueous and organic phase.

An SAP catalyst is depicted in FIGS. 1A-1D. SAP catalysts generallycomprise a solid support 1 possessing a surface 2 and an aqueoussolution 3 containing the water soluble organometallic catalyst 4. Thesolid support 1 is able to immobilize the aqueous solution of thecatalyst on the surface of the support. Thus, when a water solubleorganometallic catalyst is introduced, the catalyst is immobilizedwithin the aqueous solution contained on the surface of the solidsupport. Highly polar solvents, such as ethylene glycol, may be used inplace of the aqueous solution 3 to solubilize the organometalliccatalyst and to immobilize the organometallic catalyst within the SAPcatalyst.

One advantage of SAP catalysts is the simplicity of catalyst recovery.When a SAP catalyst is used in a water immiscible organic solvent 5, theorganometallic catalyst is retained within the aqueous solutionimmobilized on the surface of the solid support 1 and thus can be easilyrecovered by simple filtration.

The design, synthesis and use of supported aqueous phase organometalliccatalysts is described in Davis, et al., U.S. Pat. No. 4,994,427, Davis,et al., U.S. Pat. No. 4,947,003, and Davis, Chemtech (1992) 22:498-502,each of which is incorporated herein by reference.

In order for a catalyst in a supported aqueous phase organometalliccatalyst system or two phase system to be effective, the organometalliccatalyst must be both soluble and active in water. In the case where ahighly polar solvent, such as ethylene glycol, is used instead of water,the catalyst must be both soluble and active in the highly polarsolvent.

Water solubilization of organometallic catalysts is generally performedby modifying the phosphine ligands to include highly polar functionalgroups such as amino, carboxylic acid, hydroxy, ether and sulfonategroups. Joo, et al., J. Mol. Catal. (1980) 8:369; Sinou, Bull. Soc.Chim. Fr. (1987) 480; Kalck, et al., Adv. Organomet. Chem. (1992)34:219.

Water-soluble organometallic catalysts provide the added advantage ofsynthetic flexibility by enabling one to conduct reactions in an aqueoussystem, an organic-aqueous two phase system (Kalck, et al., Adv.Organomet. Chem. (1992) 34:219; Toth, et al., Catal. Lett. (1990) 183;Toth, et al., Tetra. Asym. (1990) 1:913) or as a supported aqueous phasecatalyst in an organic solvent (Arhancet, et al., Nature (1989) 339:454;Arhancet, et al., J. Catal. (1990) 121:327; Arhancet, et al., J. Catal.(1991) 129:94; Arhancet, et al., J. Catal. (1991) 129:100; Davis,Chemtech (1992) 22:498).

Dang, et al., U.S. Pat. No. 4,654,176, describes the sulfonation ofseveral chiral phosphines in order to render those catalysts watersoluble. Dang, et al. notes that these catalysts enable reactions to becarried out in a medium comprising water and an appropriate organicsolvent.

Unfortunately, sulfonation of chiral phosphine ligands has been found toresult in a loss of enantioselectivity. Amrani, et al., J. Mol. Catal.(1984) 24:231; Lecomte, et al., J. Organomet. Chem. (1989) 37:277.Therefore, the need exists for an asymmetric catalyst whoseenantioselectivity is not decreased when the catalyst is modified topossess greater water solubility.

A significant loss in enantioselectivity is also observed when water isused as the solvent. Toth, et al., Tetra. Asym. (1990) 1:913; Amrani, etal., J. Mol. Catal. (1984) 24:231; Sinou, et al., J. Mol. Catal. (1986)36:319; Benhanza, et al., J. Organomet. Chem. (1985) 288:C37; Lecomte,et al., J. Organomet. Chem. (1989) 370:277; Oehme, et al., J. Mol.Catal. (1992) 71:L1. The need therefore exists for a catalyst thatfunctions in neat water without significant loss in enantioselectivity.

SUMMARY OF THE INVENTION

The present invention relates to water soluble chiral sulfonated2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and its use asorganometallic catalysts for asymmetric synthesis of optically activecompounds. Asymmetric reactions of the present invention include, butare not limited to, those reactions in which organometallic catalystsare commonly used. Such reactions include reduction and isomerizationreactions on unsaturated substrates and carbon-carbon bond formingreactions. Examples of such reactions include, but are not limited to,hydrogenation, hydroboration, hydrosilylation, hydride reduction,hydroformylation, alkylation, allylic alkylation, arylation,alkenylation, epoxidation, hydrocyanation, disilylation, cyclization andisomerization reactions.

The catalysts of the present invention provide the advantage offunctioning in the presence of water without loss in enantioselectivityrelative to the nonsulfonated BINAP catalyst in an organic solvent. As aresult, the catalysts of the present invention may be employed in water,water miscible solvents, in aqueous-organic two phase solvent systemsand in supported aqueous phase catalysts in organic solvents withoutloss in enantioselectivity. Further, the catalysts of the presentinvention may also be effectively employed in highly polar solvents suchas primary alcohols and ethylene glycol.

The present invention also relates to a method for conducting asymmetricreactions on prochiral unsaturated bonds contained within a compoundusing the water soluble chiral sulfonated2,2'bis(diphenylphosphino)-1,1'-binaphthyl organometallic catalysts ofthe present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D depict a supported aqueous phase catalyst (SAP).

FIG. 2 depicts the preferred BINAP organometallic catalyst of thepresent invention, Ru(benzene)(Cl)(BINAP-4SO₃ Na)! Cl.

FIG. 3 depicts the mechanistic basis for enantioselectivity dependenceon substrate concentration in the parent rhodium-BINAP catalyst.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention relates to water soluble chiral sulfonated2,2'-bis(diphenylphosphino)-1,1'binaphthyl (BINAP-SO₃ Na) ligands andtheir use as water soluble organometallic catalysts in the asymmetricsynthesis of optically active compounds.

It is preferred that the chiral sulfonated binaphthyl be tetrasulfonated(BINAP-4SO₃ Na). Metals used to form the catalysts of the presentinvention include those metals used in catalysts for the asymmetricreactions of the present invention. Such metals include, but are notlimited to, rhodium, ruthenium, iridium, vanadium, lead, platinum, tin,nickel or palladium. With regard to hydrogenation reactions, rutheniumis the most preferred metal. It is also preferred that the catalystcomprise a counterion, most preferably Na⁺, K⁺, Cs⁺ and Ca²⁺. Thepreferred sulfonated BINAP catalyst of the present invention,Ru(benzene)(Cl)(BINAP-4SO₃ Na)! Cl, is depicted in FIG. 2.

Asymmetric reactions of the present invention include those reactions inwhich organometallic catalysts are commonly used. Such reactionsinclude, but are not limited to, reduction and isomerization reactionson unsaturated substrates and carbon-carbon bond forming reactions.Examples of such reactions include, but are not limited to,hydrogenation, hydroboration, hydrosilylation, hydride reduction,hydroformylation, alkylation, allylic alkylation, arylation,alkenylation, epoxidation, hydrocyanation, disilylation, cyclization andisomerization reactions. In these reactions, a catalyst is generallyused to catalyze the enantioselective transformation of a prochiralunsaturated substrate. Types of prochiral unsaturated substratesasymmetrically reacted using the sulfonated BINAP catalysts of thepresent invention include, but are not limited to, alkenes, aldehydes,ketones, thioketones, oximes, imines, enamines, allylic alcohols,allylamines and unsaturated carboxylic acids.

The present invention also relates to water soluble chiralorganometallic catalysts that comprise a sulfonated BINAP ligand and ametal useful for catalyzing asymmetric reactions. Metals used to formthe catalysts of the present invention include those metals used incatalysts for the asymmetric reactions of the present invention. Suchmetals include, but are not limited to, rhodium, ruthenium, iridium,vanadium, lead, platinum, tin, nickel or palladium.

The present invention also relates to a method for conducting anasymmetric reaction on a prochiral unsaturated bond using a watersoluble organometallic catalyst that comprises a chiral sulfonated BINAPligand of the invention.

The sulfonated catalysts of the present invention are soluble in water,water miscible solvents and highly polar solvents such as primaryalcohols and ethylene glycol. The sulfonated catalysts are not solublein nonpolar solvents such as hexane. As a result, the catalysts of thepresent invention may be employed in water, in the aqueous phase of anaqueous/organic two phase system, in water miscible organic solventssuch as methanol, ethanol, propanol, ethylene glycol anddimethylsulfoxide as well as in water immiscible solvents where thecatalyst is solubilized in an aqueous solution which is in turnimmobilized on the surface of a supported aqueous phase catalyst. Ineach case, the sulfonated catalysts of the present invention aregenerally solvated by water molecules and thus catalyze asymmetricreactions in the presence of water. It should be understood that highlypolar solvents, such as ethylene glycol, may be used in place of waterin two phase and SAP catalyst systems.

Surprisingly, the sulfonated catalysts of the invention exhibit nosignificant loss in enantioselectivity in water as compared to thecorresponding nonsulfonated catalyst in an organic solvent. In contrast,Amrani, et al., J. Mol. Catal. (1984) 24:231 and Lecomte, et al., J.Organomet. Chem. (1989) 370:277 teach that significantenantioselectivity is lost when sulfonated phosphine catalysts areemployed in the presence of water.

As used herein, an enantioselective reaction is one where oneenantiotopic face is selectively attacked over the other thereby causingthe formation of one enantiomer over another. Enantiomeric excess (e.e.)is a measurement of a reaction's enantioselectivity and is defined bythe quantity ##EQU1## where R and S are relative quantities of R and Senantiomers.

The asymmetric catalysts of the present invention are preferably used ina supported aqueous phase catalyst system because of the ease ofcatalyst recovery and because SAP catalysts exhibit higher activity dueto an increased surface area than the same catalysts in the two-phasesystem.

It has been observed that the enantioselectivity of the rhodium basedsulfonated BINAP catalysts is not effected by the substrateconcentration. This can be explained by the proposed mechanism for thesubstrate concentration dependent enantioselectivity of the rhodiumbased non-sulfonated BINAP catalyst which is depicted in FIG. 3.

As depicted in FIG. 3, when the substrate concentration is increased,the concentration of the 1:2 catalyst:substrate adduct increases. Uponhydrogenation, the 1:2 adduct produces products with decreasedenantioselectivity because chelation of the substrate to the catalyst islost and/or one of the metal-phosphorus bonds is broken upon theformation of the 1:2 adduct. This results in a decreasedenantioselective interaction between the substrate and the catalyst. Bycontrast, it is believed that the sulfonated BINAP catalyst cannot formthe corresponding 1:2 adduct due to steric hinderance caused by thesulfonate groups. This would explain why no substrate concentrationeffects regarding enantioselectivity are observed.

As can be seen from the data presented in Table 3, theenantioselectivity of the rhodium based sulfonated BINAP catalystsappears to increase with increases in the water concentration of thesolvent. In the case of other sulfonated phosphine catalysts, decreasedenantioselectivity is generally observed when the water concentration ofthe solvent is increased.

Ruthenium based sulfonated BINAP catalysts possess the oppositeenantioselectivity as the rhodium based catalysts using the sameenantiomer of the BINAP ligand. However, it should be noted that bothenantiomeric products can be selectively produced using both rutheniumand rhodium based catalysts by using either the (R)- or (S)- enantiomerof the BINAP ligand. Ruthenium based sulfonated BINAP catalysts arepreferred because they exhibit enantioselectivity superior to thecorresponding rhodium catalysts. Further, the parent nonsulfonatedruthenium BINAP catalyst has been shown to catalyze a wider range ofreactions than the corresponding nonsulfonated rhodium BINAP catalyst.Asymmetric reactions that have been conducted using the nonsulfonatedruthenium BINAP catalyst include but are not limited to hydrogenation,hydroboration, hydrosilylation, hydride reduction, hydroformylation,alkylation, allylic alkylation, arylation, alkenylation, epoxidation,hydrocyanation, disilylation, cyclization and isomerization.

The ruthenium sulfonated BINAP catalysts are also preferred because theyexhibit higher stability, although less catalytic activity, than rhodiumsulfonated BINAP catalysts.

The following examples set forth the synthesis and application of thechiral sulfonated BINAP catalysts of the present invention. Thefollowing examples also set forth the method by which the preferredembodiments were determined. It is understood that reactions relating toeither the (R)- or (S)- BINAP catalyst can be equally employed using theother enantiomer. Therefore, specific recitation to (R)- or (S)- BINAP,or derivatives thereof, are not intended to be limiting. Furtherobjectives and advantages of the present invention other than those setforth above will become apparent from the examples which are notintended to limit the scope of the present invention.

EXAMPLES 1. Sulfonation of (R)-BINAP under Conditions that Minimize theFormation of Phosphine Oxides and Maximize the Degree of Sulfonation

Sulfonation of (R)-BINAP is preferably performed under conditionsdesigned to eliminate the formation of phosphine oxides and to achieve ahigh yield of a single phosphine species. Table 1 summarizes the resultsfrom sulfonating (R)-BINAP under a variety of reaction conditions.

                  TABLE 1                                                         ______________________________________                                              Time    Temp.                                                            SO.sub.3 !%                                                                        (days)  (°C.)                                                                          Products*                                               ______________________________________                                        30    5       22      55% mixture of sulfonated products + 45%                                      oxides                                                  30    4       50      100% oxides                                             25    3        0      100% oxides                                             50    5       <10     70% mixture of sulfonated products 30%                                        oxides                                                  43    4.5     10      single major sulfonated product + 5% oxides             40    3        0      single major sulfonated product                         ______________________________________                                         *(based on .sup.31 P NMR signals)                                        

Based on the test results summarized in Table 1, the followingsulfonation protocol was designed in order to minimize the formation ofphosphine oxides and to selectively produce the tetra-sulfonated BINAPderivative. First, 1 g of (R)-BINAP was dissolved in 3.5 ml ofconcentrated sulfuric acid at 10° C. under argon. Afterward, 15 ml offuming sulfuric acid (40 wt % sulfur trioxide in concentrated sulfuricacid) was added dropwise over 2-3 hours. The resulting solution was thenstirred at 10° C. under an argon atmosphere for 3 days. In the eventthat the reaction mixture solidifies, it is preferred that a stepwiseaddition of sulfur trioxide be used rather than a dropwise addition inorder to prevent solidification.

After stirring, the reaction was quenched by pouring the sulfuric acidsolution into 100 ml of ice cooled water followed by the dropwiseaddition of 50 wt % NaOH until the solution was neutralized to pH 7. Theresulting aqueous solution was then reduced to 30 ml under vacuum. 100ml of methanol was then added to the concentrated solution in order toprecipitate any sodium sulfate present in solution. The sodium sulfatewas removed by filtration and the supernatant reduced under vacuum toyield a solid. The solid was then dissolved in neat methanol to removetrace amounts of sodium sulfate to yield sulfonated (R)-BINAP in a70-75% yield.

Complete removal of sodium sulfate was confirmed by ³³ S NMR. Thepresence of sodium sulfate in the isolated solid was measured byoxidizing the sample followed by analyzing the sample using ³³ S NMR inD₂ O. No sodium sulfate was detected after 150,000 NMR scans. No furtherinformation regarding the sample's composition could be obtained due tothe fact that the sulfate groups on the sulfonated BINAP give a broadpeak around -13 ppm relative to ammonium sulfate.

Elemental analysis of the resulting product indicated that it wasapproximately 85% tetrasulfonated BINAP (BINAP-4 SO₃ Na: CalculatedS/P:Na/P:C/Na=2:2:11; Found S/P:Na/P:C/Na=2.34:2.02:11.31). The productwas then analyzed by ³¹ P NMR which showed a single major resonance at-11.1 ppm and a second smaller resonance at -12.7 ppm (relative to H₃PO₄), the two resonances having intensity ratios of 86:14. The presenceof a single major ³¹ P resonance indicates that the product issymmetrical about each phosphorous atom. Equivalent phosphorous atomresonances would be expected if each phenyl ring of the BINAP ligand issulfonated, thereby creating a symmetrical molecule. Thus, it isbelieved that each phenyl ring of the BINAP ligand is monosulfonated.

It is believed that sulfonation occurs on the phenyl rings rather thanthe naphthyl rings due to a difference in the π-stabilization energy ofthe aromatic rings, thereby causing the phenyl rings to be more reactivetoward electrophilic aromatic substitution by sulfur trioxide than thenaphthyl rings. This hypothesis is supported by the observation of asingle major ³¹ p NMR signal. At least two NMR resonances having equalintensities would appear in the ³¹ p spectrum of a tetra-sulfonatedBINAP if the naphthyl ring was also sulfonated. Nonetheless, definitiveassignments are not possible due to the complexity of the ¹ H and ¹³ CNMR spectra.

It is believed that the second minor NMR resonance observed correspondsto penta- and hexa-sulfonated BINAP derivatives where the additionalsulfonate groups appear on the naphthyl rings. Production of highersulfonated BINAP derivatives is not expected to adversely impactenantioselectivity since enantioselectivity is believed to be based onthe interaction of the phenyl rings with the substrate and not thenaphthyl rings. The observation of similar activity and selectivitybetween separately prepared batches of ligands having different major tominor species ratios appears to confirm the hypothesis thatenantioselectivity is not adversely affected by sulfonation of thenaphthyl rings.

2. Preparation of Rhodium BINAP-4 SO₃ Na Catalyst

The rhodium BINAP-4 SO₃ Na catalyst was prepared by reactingRh(COD)Cl!₂, wherein COD represents cycloocta-1,5-diene, with twoequivalents of (R)-BINAP-4SO₃ Na in water at room temperature in thepresence of excess sodium perchlorate to form the cationic species Rh(R)-BINAP-4 SO₃ Na!(COD)!(ClO₄). Exposure of Rh (R)-BINAP-4 SO₃Na!(COD)!(ClO₄) to one atmosphere of dihydrogen yields the activecatalyst Rh (R)-BINAP-4 SO₃ Na! (H₂ O)₂ !⁺. The rhodium BINAP-4 SO₃ Nacatalyst may also be prepared in methanol to yield the active catalystRh (R)-BINAP-4 SO₃ Na! (methanol)₂ !⁺. Further addition of twoequivalents of (R)-BINAP-4 SO₃ Na or the initial admixture of fourequivalents of Rh(COD)Cl!₂ yields the inactive complex Rh (R)-BINAP-4SO₃ Na!₂ !⁺. Assignments for these species are based on the datapresented in Table 2.

                  TABLE 2                                                         ______________________________________                                        .sup.31 P NMR data for various ligands and rhodium complexes                  Compound     Solvent       δ(ppm).sup.1                                                                    J.sub.Rh-p (Hz)                            ______________________________________                                        BINAP-4SO.sub.3 Na(L)                                                                      D.sub.2 O     -11.0(s)                                                                              --                                          Rh(L)COD!ClO.sub.4                                                                        D.sub.2 O     31.0(d) 144                                         Rh(L)(D.sub.2 O).sub.2 !ClO.sub.4                                                         D.sub.2 O     51.0(d) 196                                        (S)-BINAP (L')                                                                             C.sub.6 D.sub.6 :CD.sub.3 OD(4:1)                                                           -12.8(s)                                                                              --                                          Rh(L')(NBD)!ClO.sub.4                                                                     CD.sub.3 OD   25.1(d) 156                                         Rh(L')(CH.sub.3 OH).sub.2 !CLO.sub.4                                                      CD.sub.3 OD   53.1(d) 206                                        (S,S)-cyclobutanediop-                                                                     D.sub.2 O     -20.2(s)                                                                              --                                         (L")-4SO.sub.3 Na                                                              Rh(COD)Cl!.sub.2 +(L")                                                                    D.sub.2 O     20.2(d) 144                                         Rh(L")(H.sub.2 O).sub.2 !.sup.+                                                           D.sub.2 O     43.5(d) 182                                        (S,S)-BDPP(L' ' ')-                                                                        D.sub.2 O     0.7(s)  --                                         4So.sub.3 Na                                                                   Rh(COD)Cl!.sub.2 +L' ' '                                                                  D.sub.2 O     29.3(d) 144                                         Rh(L' ' ')(H.sub.2 O).sub.2 !.sup.+                                                       D.sub.2 O     53.2(d) 185                                        ______________________________________                                         .sup.1 31 P NMR chemical shifts relative to 85 wt % H.sub.3 PO.sub.4 ;        downfield shifts are positive.                                           

3. Asymmetric Hydrogenation of 2-Acetamidoacrylic acid andmethyl-2-acetamidoacrylate Using Rh (R)-BINAP-4 SO₃ Na! (H₂ O)₂ !⁺

Asymmetric hydrogenation of 2-acetamidoacrylic acid andmethyl-2-acetamidoacrylate using Rh (R)-BINAP-4 SO₃ Na! (H₂ O)₂ !⁺ wasconducted at room temperature and one atmosphere of dihydrogen in batchautoclaves. Hydrogenation of the alkene was measured by ¹ H NMR. Theenantiomeric excesses of the products were determined by firstderivatizing the amino acids to N-trifluoroacetyl amino acids accordingto El Baba, et al., Tetrahedron (1984) 40:4275. The resultingN-trifluoroacetyl amino acids were then separated and analyzed by gaschromatography using a J & W Scientific CDX B chiral capillary column.

As depicted in Table 3, the (S) enantiomers of 2-acetamidoacrylic acidand methyl-2-acetamidoacrylate are preferentially formed using the Rh(R)-BINAP-4 SO₃ Na! (H₂ O)₂ !+ catalyst. Hence, Rh (R)-BINAP-4 SO₃ Na!(H₂ O)₂ !+ provides the same enantioselectivity as the non-sulfonatedrhodium BINAP catalyst. Miyashita, et al., Tetrahedron (1984) 40:1245.

                  TABLE 3                                                         ______________________________________                                        Reduction of 2-acetamidoacrylic acid                                          and methyl-2-acetamidoacrylete using                                          {Rh (R)-BINAP-4SO.sub.3 Na! (solvent).sub.2 } (ClO.sub.4)                     at room temperature under 1 atm. of H.sub.2                                   Substrate       Solvent    Conc. (M)                                                                              ee(%)                                     ______________________________________                                        2-acetamidoacrylic acid                                                                       methanol   0.078    58.0                                      "               "          0.017    58.0                                      "               "          0.003    57.5                                      "               "          0.007    70.4                                      methyl-2-acetamidoacrylate                                                                    "          0.134    50.8                                      "               "          0.017    47.8                                      "               "          0.003    49.0                                      "               water      0.039    68.8                                      "               "          0.017    68.5                                      ______________________________________                                    

Unexpectedly, the sulfonated BINAP catalyst exhibits roughly the sameenantioselectivity in neat water (70.4-68.0%) as was observed by A.Miyashita, et al. using the unsulfonated BINAP catalyst in ethanol(67.0%). Miyashita, et al., Tetrahedron (1984) 40:1245. This issurprising since sulfonation of phosphine ligands generally results in aloss of enantioselectivity.

The sulfonated rhodium BINAP catalysts of the present invention arefurther distinguishable from the corresponding non-sulfonated BINAPcatalysts by the fact that enantioselectivity is substrate concentrationindependent as shown by the data presented in Table 3.

Without being bound by theory, the observed substrate concentrationindependence is believed to be due to the bulky sulfonated phenyl ringsof the BINAP ligand which inhibit the formation of a 1:2catalyst:substrate adduct. As depicted in FIG. 3, enantioselectivity islost when a 1:2 catalyst:substrate adduct forms. When the phenyl ringsof the BINAP ligand are not sulfonated, there is less steric hinderanceto prevent the formation of a 1:2 catalyst:substrate adduct. Thus, athigher substrate concentrations, the population of the 1:2catalyst:substrate adduct increases and results in lowerenantioselectivity. By contrast, the added steric bulk created by thesulfonate groups on the phenyl rings inhibits the formation of the 1:2catalyst:substrate adduct at higher substrate concentrations. As aresult, the enantioselectivity of the sulfonated catalysts of thepresent invention exhibits substrate concentration independence.

The substrate concentration independence of the sulfonated catalysts ofthe present invention enable the use of these catalysts to be scaled upbecause increases in substrate concentration do not adversely impactenantioselectivity. By contrast, scale-up using the non-sulfonated BINAPcatalyst has been limited by the adverse impact increases in substrateconcentration have on enantioselectivity.

In addition to exhibiting enantioselectivity that is substrateconcentration independent and showing the same enantioselectivity inneat water as the unsulfonated BINAP catalyst in ethanol, the sulfonatedrhodium BINAP catalysts of the present invention also do not exhibit thesame loss in enantioselectivity that is generally observed when water isused as a solvent. As shown in Table 4, the enantioselectivity of thesulfonated rhodium BINAP catalysts of the present invention actuallyincreases with increases in the water concentration. The same trend inenantioselectivity was observed using both 2-acetamidoacrylate and itscorresponding methyl ester as substrates. As can be seen from the datain Table 4, the enantioselectivity of the sulfonated rhodium BINAPcatalysts of the present invention when used in water is contrary to theenantioselectivity prior art sulfonated chiral catalysts.

                                      TABLE 4                                     __________________________________________________________________________    Substrate         Solvent  Conc. (M)                                                                          ee %                                          __________________________________________________________________________    Rh (R)-BINAP-4SO.sub.3 Na!(solvent).sub.2 (ClO.sub.4)                         2-acetamidoacrylic acid                                                                         water    0.007                                                                              70.4(S)                                          "              7:1 water/methanol                                                                     0.017                                                                              67.0(S)                                          "              1:1 water/methanol                                                                     0.017                                                                              56.0(S)                                          "              1:2 water/methanol                                                                     0.042                                                                              55.0(S)                                          "              methanol 0.017                                                                              58.0(S)                                       methyl-2-acetamidoacrylic acid                                                                  water    0.017                                                                              68.5(S)                                          "              4:2 water/methanol                                                                     0.017                                                                              61.2(S)                                          "              1:1 water/methanol                                                                     0.017                                                                              42.1(S)                                          "              methanol 0.017                                                                              47.8, 47.3(S)                                  Rh(R-BINAP)(solvent).sub.2 !.sup.+                                           methyl-2-acetamidoacrylic acid                                                                  ethanol  N.R. 67.0*                                          Rh(COD)1A!(ClO.sub.4)‡                                            acetamidocinnamic acid                                                                          methanol 0.1  80.0(S)                                          "              1:9 water/methanol                                                                     0.1  75.5(S)                                          "              3:7 water/methanol                                                                     0.1  70.0(S)                                          "              1:1 water/methanol                                                                     0.1  63.5(S)                                          "              ethanol  0.1  82.0(s)                                          "              1:4 water/ethanol                                                                      0.1  77.0(S)                                          "              2:3 water/ethanol                                                                      0.1  75.0(S)                                          "              3:2 water/ethanol                                                                      0.1  70.0(S)                                       methyl-acetamidocinnamic acid                                                                   methanol 0.1  50.0(S)                                          "              1:9 water/methanol                                                                     0.1  47.0(S)                                          "              3:7 water/methanol                                                                     0.1  40.0(S)                                          "              1:1 water/methanol                                                                     0.1  35.0(S)                                          "              7:3 water/methanol                                                                     0.1  27.0(S)                                        Rh(COD)2B)! (ClO.sub.4)‡                                          acetamidocinnamic acid                                                                          ethanol  0.1  73.0(S)                                          "              3:17 water/ethanol                                                                     0.1  70.0(S)                                          "              1:3 water/ethanol                                                                      0.1  68.0(S)                                          "              1:1 water/ethanol                                                                      0.1  63.0(s)                                          "              4:1 water/ethanol                                                                      0.1  43.0(S)                                          "              water    0.1  33.0(S)                                       __________________________________________________________________________     N.R. = not reported.                                                          *Miyashita, et al., Tetrahedron (1984) 40:1245.                               ‡Data for these catalysts from Lecomte, et al., J. Organomet.      Chem. (1989) 370:277.                                                         ##STR1##                                                                      ##STR2##                                                                      ##STR3##                                                                 

4. Comparison of Initial Turnover Rates of Sulfonated and NonsulfonatedCatalysts

Comparison of the turnover rates of sulfonated and nonsulfonated(R-BINAP) rhodium catalysts is set forth in Table 5. A significantdecrease in the catalyst turnover rate is observed when water is used asthe solvent. This is believed to be due to the lower solubility ofdihydrogen in water. The solubility of dihydrogen in ethanol and waterat 25° C. at 1 atm. is 38.2×10⁻⁴ M and 8.53×10⁻⁴ M respectively. Despitethe lower turnover rate, reasonable activity in neat water is achievedunder mild reaction conditions (room temperature, 1 atm).

                  TABLE 5                                                         ______________________________________                                                                     Turnover ee                                      Catalyst             Solvent (hr.sup.-1)                                                                            (%)*                                    ______________________________________                                         Rh (R)-BINAP-4SO.sub.3 Na!(solvent).sub.2 !(ClO.sub.4)                                            water    41      69                                       Rh (R)-BINAP-4SO.sub.3 Na!(solvent).sub.2 !(ClO.sub.4)                                            ethanol 302      56                                       Rh (R)-BINAP!(solvent)(ClO.sub.4)THF.sup.b                                                        ethanol 389      20                                       Rh (R)-BINAP!(solvent)(ClO.sub.4)                                                                 ethanol 467      22                                       Rh (R)-BINAP!(solvent)(ClO.sub.4)THF.sup.b,c                                                      ethanol 264      35                                       Rh (R)-BINAP-4SO.sub.3 Na!(solvent).sub.2 !(ClO.sub.4)                                            water    45      68                                      ______________________________________                                         Substrate: methyl2-acetamidoacrylate                                          Conditions: T = 23° C.; P = 1 atm                                      .sup.a  substrate!/ Rh! = 76; chemical yield quantitative                     .sup.b from Aldrich                                                           .sup.c 2acetamidoacrylic acid as substrate                                    .sup.d from a different batch of ligand                                       *at 100% conversion                                                      

5. Preparation of Ruthenium BINAP-4 SO₃ Na Catalyst

The ruthenium BINAP-4 SO₃ Na catalyst was prepared by reactingRu(benzene)Cl₂ !₂ with two equivalents of (R)-BINAP-4SO₃ Na in a 1:8benzene/methanol solvent to yield Ru(benzene)Cl (R)-BINAP-4 SO₃ Na!!Cl.³¹ p NMR (CD₃ OD): d.d. δ=63.0, δ 68.8 ppm J=45 Hz. Specifically, 0.001g of Ru(benzene)Cl₂ !₂ was stirred with 0.0050 g BINAP-SO₃ Na in 4.5 mlof a 1:8 benzene/methanol solvent at 55° C. under argon for 1-2 hours.The resulting solution was then vacuum dried at room temperature.

Interestingly, reacting Ru(benzene)Cl₂ !₂ with two equivalents of(R)-BINAP-4SO₃ Na in water at 55°-60° C. for 2 hours did not yield ahighly active catalyst for hydrogenation. The ³¹ p NMR spectrum of theresulting product contained two peaks in strictly a 1:1 ratio ³¹ p NMR(D₂ O): d=57.5 and 63.7 ppm!. From the difference in line shape, the tworesonances appear to be originating from different phosphorous atoms. A² Jpp coupling could not be observed in water. Because P--C bondcleavage of Rh-phosphine complexes is well known (Abatjoglou, et al.,Organometallics (1984) 3 923), it is speculated that a similar oxidativeaddition of the phosphorous-naphthyl bond to the Ru center is occurring.Since the oxidative addition of a P--C bond from a phosphine to atransition metal center is promoted by the presence of a vacantcoordination site, a weakly coordinating agent, such as an aromaticsolvent, can be used to suppress oxidation addition of a P--C bond.

6. Asymmetric Hydrogenation Using ruthenium (R)-BINAP Catalyst

Asymmetric hydrogenation of 2-acetamidoacrylic,methyl-2-acetamidoacrylate and 2-acetamidocinnamic acid was performedusing the sulfonated ruthenium BINAP catalysts prepared according toExample 5. The results of the hydrogenation are set forth in Table 6.

                  TABLE 6                                                         ______________________________________                                        Substrate    Solvent    Pressure                                                                              T(°C.)                                                                       ee%                                     ______________________________________                                        Ru.sub.2 Cl.sub.4 (BINAP).sub.2 (Et.sub.3 N)                                  2-acetamidoacrylic acid                                                                    1:1 ethanol-                                                                             2       35    76.0(R).sup.1                                        THF                                                              2-acetamidocinnamic                                                                        ethanol/THF/                                                                             1       RT    86.0(S)                                 acid         Et.sub.3 N                                                        Ru (benzene) (BINAP-4SO.sub.3 Na)!.sup.2+                                    2-acetamidoacrylic acid                                                                    methanol   1       RT    84.2(R)                                 2-acetamidoacrylic acid                                                                    water      1       RT    68.5(R)                                 methyl-2-acetamido-                                                                        methanol   1       RT    84.7(R)                                 acrylic acid                                                                  methyl-2-acetamido-                                                                        water      1       RT    75.9(R)                                 acrylic acid                                                                  methyl-2-acetamido-                                                                        water      1       50    82.0(R)                                 acrylic acid                                                                  2-acetamidocinnamic                                                                        methanol   1       RT    81.3(R)                                 acid                                                                          2-acetamidocinnamic                                                                        1:1 methanol:                                                                            1       RT    84.0(R)                                 acid         water                                                            2-acetamidocinnamic                                                                        water      1       RT    87.7(R)                                 acid                                                                          2-acetamidocinnamic                                                                        ethanol    1       RT    80.1(R)                                 acid                                                                          ______________________________________                                         .sup.1 Data from Kawano, et al., J.C.S. Perkin Trans. I, (1989) 1571.    

As can be seen from the results depicted in Table 6, the rutheniumcatalysts of the present invention possess the oppositeenantioselectivity as rhodium based sulfonated BINAP catalysts using thesame BINAP enantiomer. The data from Table 6 also indicates that theenantioselectivity of ruthenium based sulfonated BINAP catalysts, unlikethe rhodium catalysts, varies with regard to water concentrationdependence, depending on the substrate used. For example, with2-acetamidocinnamic acid, enantioselectivity increases with increases inwater concentration. By contrast, enantioselectivity with2-acetamidoacrylic acid decreases with increases in water concentration.

7. Asymmetric Hydrogenation Using Ruthenium Sulfonated BINAP Catalyst inMethanol

In contrast to most other sulfonated phosphine systems, (Amrani, et al.Organometallics (1989) 8:542; Bartik, et al. Organometallics (1993)12:164) the ruthenium sulfonated BINAP catalyst is quite soluble in neatmethanol. Methanol is known to give the highest enantiomeric excess inmany of the asymmetric reactions catalyzed by non-sulfonated complexes.

Asymmetric hydrogenation of 2-(6'-methoxy-2'-naphthyl)acrylic acid bythe non-sulfonated Ru-BINAP catalyst has been carried out in neatmethanol. Chan, et al. in "Selectivity In Catalysis" (Davis, M. E., andSuib, S. L., Eds.) Chap. 3, p. 27. ACS Symposium Series 517 (1993).Homogeneous, asymmetric hydrogenations of2-(6'-methoxy-2'-naphthyl)acrylic acid were conducted in methanolicsolvents to allow a direct comparison between the sulfonated and parentsystem.

Reductions were carried out under a hydrogen pressure of 500-1400 psig.In neat methanol, the sulfonated BINAP catalyst (96.1% at 4° C.) wasfound to be as enantioselective as the corresponding nonsulfonated BINAPcatalyst (96.0% at 0° C.), at slightly higher hydrogen pressure.

8. Asymmetric Hydrogenation in Two Phase Solvent System

Hydrogenation in a simple two-phase reaction system was performed inorder to compare catalyst performance with results using a homogeneoussolvent system as well as a SAP catalyst. Anhydrous ethyl acetate waschosen as the organic solvent. 2-(6'-methoxy-2'-naphthyl) acrylic acidwas used as the substrate. When the substrate was charged into thehydrogenation reactor along with an aqueous solution of the rutheniumcatalyst (10 ml of 1:1 ethyl acetate/water and S/C=50), a 53.6%conversion was observed in 3.5 days with an initial turnover frequencyof 0.34hr⁻¹. Table 7, Entry 1. In comparison to neat methanol, thetwo-phase reaction system is at least 350 times slower. Table 7, Entry 1and 13. The slower reaction rate is most likely due to the limitedsolubility of the substrate in water. As a result, most of the reactionis taking place at the aqueous-organic phase interface. The rate istherefore limited by the interfacial surface area between the catalystcontaining aqueous phase and the substrate containing organic phase. Aswill be discussed in Section 9, the surface area limitation of two phasesystems is significantly reduced by using a SAP catalyst which has beenfound to be 50 times more active than the two phase system. This is dueto the much larger interfacial surface area provided by the high surfacearea SAP solid support.

                  TABLE 7                                                         ______________________________________                                                               Hydrogen                                                                      Pressure                                                                             Conv. T.O.F. e.e.                               Entry                                                                              Solvent    S/C.sup.a                                                                            (psig) (%)   (hr.sup.-1).sup.b                                                                    (%)                                ______________________________________                                        1    1:1 ethyl  50     1380   53.6  0.34   78.4                                    acetate/H.sub.2 O                                                        2    1:1 ethyl  25     1360   56.7  --     81.1                                    acetate/H.sub.2 O                                                        3    1:1 ethyl  25     1360   56.4  --     70.0.sup.c                              acetate/H.sub.2 O                                                        4    1:1 ethyl  25     1370   57.0  --     82.7.sup.d                              acetate/H.sub.2 O                                                        5    1:1 ethyl  15     1365   90.0  0.20   77.2.sup.e                              acetate/H.sub.2 O                                                        6    1:1 ethyl  14     1320   100.0 --     73.0.sup.f                              acetate/H.sub.2 O                                                        ______________________________________                                         .sup.a substrate to ruthenium ratio                                           .sup.b initial turnover frequency                                             .sup.c aqueous solution recycled once                                         .sup.d aqueous solution recycled twice                                        .sup.e reaction temperature = 5° C.                                    .sup.f with added triethylamine, Et.sub.3 N/substrate = 1                

                  TABLE 7                                                         ______________________________________                                        Part 2                                                                                                Hydro-                                                                        gen                                                                           Pressure                                                                            Conv. T.O.F.                                                                              e.e.                                Entry                                                                              Solvent     S/C.sup.a                                                                            (psig)                                                                              (%)   (hr.sup.-1).sup.b                                                                   (%)                                 ______________________________________                                         7   MeOH        50     1370  N/A   --    86.0(R)                              8   MeOH        53      500  N/A   --    84.7(R)                              9   1:1 MeOH/H.sub.2 O                                                                        25     1320  N/A   --    78.9(R)                             10   1:1 MeOH/H.sub.2 O                                                                        25     1340  N/A   --    75.1(R).sup.d                       11   MeOH        25     1370  N/A   --    89.5(R).sup.d                       12   MeOH        25     1360  N/A   --    91.0(R).sup.d                       13   MeOH        101    1350  N/A   131   88.2(R)                             14   MeOH        101    1350  N/A   927   91.5(R).sup.d                       15   MeOH        51     1370  N/A   --    86.2(R).sup.e                       16   1:1 MeOH/H.sub.2 O                                                                        51     1320  N/A   --    75.7(R).sup.e                       17   1:1 MeOH/H.sub.2 O                                                                        50     1350  N/A   0.77.sup.f                                                                          --                                  18   1:1 MeOH/H.sub.2 O                                                                        52     1350  N/A   --    77.6(R).sup.g                       19   MeOH        52      500  N/A   --    87.5(R).sup.d                       20   MeOH        --      500  N/A   --    93.3(R).sup.d,h                     21   MeOH        100    1230  N/A   --    96.1(R).sup.d,i                     22   MeOH        --      500  N/A   --    96.0(R).sup.d,h,j                   ______________________________________                                         .sup.a substrate to ruthenium ratio                                           .sup.b initial turnover frequency                                             .sup.c e.e. determined at 100% conversion                                     .sup.d with added triethlamine, Et.sub.3 N/substrate = 1                      .sup.e with added sodium 3pyridinesulfonate, mSO.sub.3 Na-                    pyridine/substrate = 1                                                        .sup.f with added concentrated sulfuric acid in 10 times excess of            substrate                                                                     .sup.g with added tetrahydrofuran in 1.9 times excess of substrate            .sup.h Chan, et al., "Selectivity in Catalysis," M. E. Davis and              S.L. Snib, Eds. ACS Symposium Series 517 (1993)                               .sup.i reaction temperature = 4° C.                                    .sup.j reaction temperature = 0° C.                               

Because of the limited solubility of the substrate in water, we cannotrule out the possibility that a small portion of the conversion is byreaction in the bulk aqueous phase. A 78.4% e.e. was obtained from thetwo-phase reaction. As shown by entries 2, 3 & 4 of Table 7, recyclingof the catalyst containing aqueous phase after phase separation ispossible without any drop in enantioselectivity. The enantioselectivityranged from 78.0-82.7% over several recycles of the catalytic solution.Similar enantioselectivity but lower activities (0.20hr⁻¹) were found ata reaction temperature of 5°-6° C. Table 7, Entry 5.

9. Asymmetric Hydrogenation Using a Supported-Aqueous-Phase Catalyst

In the supported-aqueous-phase configuration, anhydrous ethyl acetate isused as the organic phase. Catalytic data obtained using the sulfonatedBINAP catalyst in a SAP system is listed in Tables 8 and 9. The turnoverrates of the SAP catalysts were significantly higher than the two-phasesystem. This is believed to be due to the much higher contact surfacearea of the SAP catalysts. When 2-(6'-methoxy-2'-naphthyl) acrylic acidwas hydrogenated with a "dried" sample of the SAP catalyst (1.9 wt %water), no detectable conversion is observed even after 70 hours at roomtemperature under 1300 psig of hydrogen pressure (T.O.F.<0.008hr⁻¹).Table 9, Entry 1. Significantly, when water-saturated ethyl acetate wasused as solvent, a 100% conversion (S/C=31.5) was achieved in ˜3 hoursunder the same reaction conditions with an initial turnover frequency of18.2hr⁻¹ and up to an 70% e.e. Table 8, Entry 5, Table 9, Entry 8. Thisenantioselectivity is only slightly lower than that found in thewater-organic two-phase system where the only difference is in thecontact surface area between the aqueous phase and the organic phase.

Similar results were also observed from other batches of SAP catalysts.Table 8, Entries 2, 6 & 9. Additionally, the enantiomeric excess of thehydrogenated product when using a SAP catalyst with 40 μl water in 10 mlof ethyl acetate as the organic solvent was found to be only 28.7% (R).Table 8, Entry 1.

Based on the results presented in Tables 8 and 9, it is evident that thewater content in the SAP catalyst has a dramatic affect on both catalystactivity and enantioselectivity. It is therefore important to have ameans for rehydrating the catalyst. Vapor-phase impregnation of wateronto the SAP solid support is not feasible for the present system sincethe ruthenium-sulfonated-BINAP catalyst is not as hydrophilic as therhodium-TPPTS catalyst developed by Wan, K. T., et al. J. Catal. (inpress); Arhancet, et al. Nature (1989) 339:454; Arhancet, et al. J.Catal. (1990) 121:327. The revised method of in-situ rehydration bywater-loaded blank support also requires higher reaction temperature(80°-100° C.) for the re-distribution of water over the SAP catalyst.Arhancet, et al. J. Catal, (1991) 129:94. This approach for loadingwater into the SAP catalyst is also not possible.

                  TABLE 8                                                         ______________________________________                                        Heterogeneous, asymmetric hydrogenation of 2-(6'-methoxy-2'-                  naphthyl) acrylic acid by SAP-Ru-BINAP-4SO.sub.3 Na catalyst in ethyl         acetate                                                                                                     Hydro-                                                                        gen   Stirring                                                                Pressure                                                                            Speed                                     Entry                                                                              Cycle.sup.a                                                                           Solvent     S/C.sup.b                                                                          (psig)                                                                              (rpm) e.e (%)                             ______________________________________                                         1   0       AcOEt (40μlH.sub.2 O)                                                                  25   1300  350   28.7 (R)                             2   0       AcOEt (H.sub.2 O sat.)                                                                    33   1300  350   69.0 (R).sup.c                       3   1       AcOEt (H.sub.2 O sat.)                                                                    30    500  350   68.3 (R)                             4   1       AcOEt (H.sub.2 O sat.)                                                                    25   1330  350   68.6 (R).sup.c                       5   2       AcOEt (H.sub.2 O sat.)                                                                    25   1330  350   70.0 (R).sup.c                       6   0       AcOEt (H.sub.2 O sat.)                                                                    30   1360  300   67.0 (R)                             7   1       AcOEt (H.sub.2 O sat.)                                                                    30   1360  300   67.0 (R)                             8   2       AcOEt (H.sub.2 O sat.)                                                                    31   1360  300   66.0 (R)                             9   0       AcOEt (H.sub.2 O sat.)                                                                    30   1330  500   69.0 (R)                            10   1       AcOEt (H.sub.2 O sat.)                                                                    30   1250  500   65.0 (R)                            11   2       AcOEt (H.sub.2 O sat.)                                                                    30   1050  550   66.0 (R)                            12   3       AcOEt (H.sub.2 O sat.)                                                                    30   1260  350   77.0 (R).sup.d                      13   5       AcOEt (H.sub.2 O sat.)                                                                    31   1360  350   62.8 (R).sup.e                      14   6       AcoEt (H.sub.2 O sat.)                                                                    30   1350  350   63.6 (R)                            15   7       AcOEt (H.sub.2 O sat.)                                                                    30   1370  350   64.6 (R).sup.c,e                    16   0       AcOEt (200μl-                                                                          30   1380  350   62.8 (R).sup.f                                   NaOH)                                                            17   1       AcOEt (NaOH 30   1380  350   59.9 (R).sup.f                                   sat.)                                                            18   2       AcOEt (NaOH 30   1000  350   59.8 (R).sup.f                                   sat.)                                                            19   3       AcOEt (NaOH 30    500  350   58.6 (R).sup.f                                   sat.)                                                            20   4       AcOEt (H.sub.2 O sat.)                                                                    30   1350  350   62.7 (R)                            ______________________________________                                         .sup.a number of catalyst recycles                                            .sup.b substrate to ruthenium ratio                                           .sup.c no ruthenium found in the filtrate with a detection limit              of 1 ppm                                                                      .sup.d reaction temperature = 8° C.                                    .sup.e with added triethylamine, Et.sub.3 N/substrate = 1                     .sup.f with 0.22 M sodium hydroxide solution                             

                  TABLE 9                                                         ______________________________________                                        Catalytic activity as a function of water content in the                      heterogeneous, asymmetric hydrogenation of 2-(6'-methoxy-2'-                  naphthyl) acrylic acid by SAP-Ru-BINAP-4SO.sub.3 Na catalyst in ethyl         acetate.                                                                                      Hydrogen     Water                                                            Pressure     Content                                                                              T.O.F.                                    Entry    S/C.sup.a                                                                            (psig)       (μl).sup.b                                                                        (Hr.sup.-1).sup.c                         ______________________________________                                        1        33     1330          0     <0.008                                    2        25     1130          40    0.22                                      3        30     1350         125    0.25.sup.d                                4        30     1360         145    1.06.sup.d                                5        31     1370         160    2.35.sup.d                                6        30     1400         195    2.84.sup.d                                7        30     1370         215    5.12.sup.d                                8        32     1370         270    18.21.sup.d                                                            (saturated)                                      ______________________________________                                         .sup.a substrate to ruthenium ratio                                           .sup.b hydrogenations were carried out in 10 ml of ethyl acetate at           room temperature and with 350 rpm stirring speed,                              substrate! = 4.6-4.8 × 10.sup.-3 M                                     .sup.c initial turnover frequency                                             .sup.d no ruthenium found in the filtrate with a detection                    limit of 1 ppm.                                                          

Organic-phase impregnation was developed as a rehydration procedure.This process is more feasible for sulfonated BINAP SAP catalysts,especially in terms of scale-up. Organic-phase impregnation isaccomplished by rehydrating "dried" SAP catalyst that has beenpreviously premixed with a controlled amount of water. Unexpectedly, inorder to achieve reasonable activity (Table 9), the amount of wateradded to the organic-phase is found to be greater than the void volumeof the support (60-70 μl). This suggests a relatively small partitioncoefficient of water between the CPG support and the ethyl acetate. Amaximum water loading of 2.8-3.1 wt % (g H₂ O/g AcOEt×100; i.e. ˜275 μlwater in 10 ml of ethyl acetate) was accomplished by using awater-saturated organic phase. The initial turnover frequencies as afunction of water content are listed in Table 9 (reaction conditions:substrate/ruthenium˜30, substrate!=4.6-4.8×10⁻³ M,pressure=1350-1400psig, T=25° C., stirring speed=350rpm). Water isintroduced to the "dried" SAP catalyst from the ethyl acetate (10 ml)and the water content controlled by adding variable amounts of water,e.g., 0, 40, 125, 145, 160, 195, 215 and 270 μl. The maximum activity,as determined by the initial turnover frequency, is observed at thehighest water content (˜3 wt % water in ethyl acetate) with an initialturnover frequency of 18.2hr⁻¹. Table 9, Entry 8. The enantioselectivityof the SAP catalyst is also dependent on the water content and shows asimilar trend to that observed in the activity; the observed range is28.7% to 70.0% (R). Table 8, Entries 1 & 5. Thus, the water contentaffects the activity and enantioselectivity of the SAP catalyst.

The present findings are quite different from that which has beenobserved in the hydroformylation of 1-octene by a SAP-rhodium-TPPTScatalyst (Arhancet, et al. J. Catal (1990) 121:327). In thehydroformylation of 1-octene, catalyst activity was much more sensitiveto the water content of the SAP catalyst with a bell-shaped curve thatdescribes the activity dependence on water content. Maximum activity wasobserved at -8 wt % (gH₂ O/g SAPC×100) water content and complete lossof activity was observed at ˜50 wt %. Arhancet, et al. J. Catal (1990)121:327.

Two factors appear to be responsible for the difference in behaviortowards the water content of these two SAP catalysts. First, theRu(benzene)(BINAP-4SO₃ Na)!²⁺ complex is stable even in neat water whileHRh(CO)(TPPTS)₃ is not stable at high syn gas pressure. At high waterloading, the HRh(CO)(TPPTS)₃ complex decomposes, resulting in a drop inactivity. Second, the decrease in the interfacial surface area of theSAP material with increasing water loading also contributes to the rapiddecline in the activity of the more hydrophilic SAP-Rh-TPPTS catalyst.Because of the small partition coefficient of water between the CPGsupport and the ethyl acetate, the actual amount of water being loadedonto the SAP-Ru-BINAP-4SO₃ Na catalyst is far below the amount added bythe vapor-phase impregnation into the much more hydrophilic SAP-Rh-TPPTScatalyst.

In view of the water content of ethyl acetate in the present SAP system,leaching of the catalytic species into the organic phase may be morelikely. Filtration of the reaction mixture to remove the solid catalystafter the hydrogenation reaction yields a colorless solution of productin ethyl acetate. All filtrates were found not to contain any rutheniumat a detection limit of 1 ppm. Table 8, Entries 2, 4-5 & 15, Table 9,Entries 3-8. In addition, in some of the experiments, filtrates weretested indirectly for the presence of ruthenium by attempting thecatalytic hydrogenation of methylenesuccinic acid using the filtratealone as catalyst. In no case was catalytic activity observed in thefiltered solutions. For example, filtered solutions gave no conversionof methylenesuccinic acid at room temperature after one day of contactunder a pressure of 30 psig of hydrogen. The inactivity of thesefiltered solutions together with the elemental analyses suggest that nosoluble ruthenium species have leached out into the organic phase.

It is reasonable to suggest that the ruthenium complex becomesincreasingly mobile as water loading increases. This is evidenced fromthe data in Table 9 which shows that the hydrated SAP catalyst is atleast 2000 times more active than the "dried" SAP catalyst. With ahigher degree of mobility, the SAP catalyst can approach the sameenantioselectivity as its counterpart in the two-phase system. Becauseof the much larger interfacial surface area between the catalystcontaining aqueous-phase and the substrate containing organic-phase, theSAP system is found to be at least 50 times more active than thetwo-phase system. In the best cases, turn over frequencies obtainedusing hydrated SAP catalyst are only seven times slower than homogeneouscatalyst in neat methanol under the same conditions. We have observed asimilar drop (6.7 times) in initial turnover frequency in thehomogeneous hydrogenation of methyl-2-acetamidoacrylate by Rh(BINAP4SO₃Na) (H₂ O)₂ !⁺ in neat water (Wan, et al. J.C.S., Chem. Commun. (1993)1262), where both the substrate and the catalyst are mixed together inone single phase. We attribute the drop in turnover frequency of therhodium system to the fact that hydrogen solubility is four to fivetimes higher in alcoholic solvents. This factor is significant since theoxidative addition of hydrogen to the rhodium catalyst is ratedetermining.

The effect of added base on the SAP system was also examined. Theresults are listed in Table 8. The addition of either aqueous sodiumhydroxide or triethylamine was found to have little effect on theenantioselectivity (Table 8, Entries 13, 15-16), although it does appearto promote the activity to some extent. In the presence of sodiumhydroxide, the enantioselectivity was found to be ratherpressure-insensitive in the pressure range of 500-1,400 psig. Table 8,Entries 17-19. The enantiomeric excesses were almost constant for thehydrated SAP catalyst in the pressure range of 500-1,400 psig. Table 8,Entries 2 & 3. Similar to the case of the homogeneous analogue, higherenantiomeric excesses (77%) are achieved with a lower reactiontemperature of 8° C., but only at the expense of activity(T.O.F.=0.43hr⁻¹). The possibility of catalyst decomposition during thesynthesis of SAP material is ruled out by the fact that a hydrogenationof 2-(6'-methoxy-2'-naphthyl) acrylic acid with an 86% e.e. wasaccomplished using a redissolved catalyst solution from a used SAPcatalyst in methanol. Thus, the ruthenium complex is still stable in theSAP configuration. It is therefore apparent that the performance of thehydrated SAP catalyst is bounded by the intrinsic enantioselectivitylimit of the ruthenium sulfonated BINAP catalyst in water. Additionally,it is clear that the SAP solid support plays no important role inenantioselectivity.

A series of reactions were carried out to test the possibility ofrecycling the SAP catalyst. The used SAP catalyst was removed from thehydrogenation mixture by simple filtration. It was then washed severaltimes with fresh ethyl acetate, followed by the addition of freshsubstrate and solvent. Similar e.e. values (65-70t%) were foundthroughout the recycling of the SAP catalyst Table 8, Entries 2, 4-5;6-8 & 9-11.

While the present invention is disclosed by reference to the preferredembodiments and examples detailed above, it is to be understood thatthese examples are intended in an illustrative rather than limitingsense, as it is contemplated that modifications will readily occur tothose skilled in the art, which modifications will be within the spiritof the invention and the scope of the appended claims.

What is claimed is:
 1. A method for conducting an asymmetric reaction toa prochiral unsaturated bond contained within a compound comprising thestep of contacting said compound with a supported highly-polarliquid-phase catalyst comprising an organometallic compound whichcomprises a metal and an enantiomerically pure chiral sulfonated2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,wherein each phenyl group ofthe sulfonated binaphthyl is monosulfonated, and wherein the degree towhich the sulfonated binaphthyl is sulfonated is selected from the groupconsisting of tetrasulfonated, pentasulfonated, and hexasulfonated. 2.The method of claim 1 wherein the highly-polar liquid-phase comprisesethylene glycol.
 3. A method according to claim 1 wherein the metal isselected from the group consisting of rhodium, ruthenium, iridium,vanadium, lead, platinum, tin, nickel and palladium.
 4. A methodaccording to claim 1 wherein the catalyst further comprises a counterionselected from the group consisting of Na⁺, K⁺, Cs⁺ and Ca²⁺.
 5. Themethod of claim 1 wherein the enantiomerically pure chiral sulfonated2,2'-bis(diphenylphosphino)-1,1'-binaphthyl is sulfonated(R)2,2'-bis(diphenylphosphino)-1,1'-binaphthyl.
 6. A method forconducting an asymmetric reaction to a prochiral unsaturated bondcontained within a compound comprising the step of contacting saidcompound with a supported highly-polar liquid-phase catalyst comprisingan organometallic compound which comprises a metal and a chiralsulfonated 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,wherein eachphenyl group of the sulfonated binaphthyl is monosulfonated, wherein thedegree to which the sulfonated binaphthyl is sulfonated is selected fromthe group consisting of tetrasulfonated, pentasulfonated, andhexasulfonated, and wherein the highly-polar liquid-phase comprisesethylene glycol.
 7. A method according to claim 6 wherein the asymmetricreaction is selected from the group consisting of hydrogenation,hydroboration, hydrosilylation, hydride reduction, hydroformylation,alkylation, allylic alkylation, arylation, alkenylation, epoxidation,hydrocyanation, cyclization and disilylation.
 8. A method according toclaim 6 wherein the metal is selected from the group consisting ofrhodium, ruthenium, iridium, vanadium, lead, platinum, tin, nickel andpalladium.
 9. A method according to claim 6 wherein the catalyst furthercomprises a counterion selected from the group consisting of Na⁺, K⁺,Cs⁺ and Ca²⁺.
 10. A method for conducting an asymmetric reaction to aprochiral unsaturated bond contained within a compound comprising thestep of contacting said compound with a supported aqueous phase catalystcomprising an organometallic compound which comprises a metal and achiral sulfonated 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,whereineach phenyl group of the sulfonated binaphthyl is monosulfonated, andwherein the decree to which the sulfonated binaphthyl is sulfonated isselected from the group consisting of tetrasulfonated, pentasulfonated,and hexasulfonated.
 11. A method according to claim 10 wherein theasymmetric reaction is selected from the group consisting ofhydrogenation, hydroboration, hydrosilylation, hydride reduction,hydroformylation, alkylation, allylic alkylation, arylation,alkenylation, epoxidation, hydrocyanation, cyclization and disilylation.12. A method according to claim 10 wherein the metal is selected fromthe group consisting of rhodium, ruthenium, iridium, vanadium, lead,platinum, tin, nickel and palladium.
 13. A method according to claim 10wherein the the catalyst further comprises a counterion selected fromthe group consisting of Na⁺, K⁺, Cs⁺ and Ca²⁺.
 14. A method ofasymmetrically hydrogenating a 2-arylacrylic acid comprising the step oftreating the 2-arylacrylic acid with hydrogen in the presence of asupported highly-polar liquid-phase catalyst comprising a metal and achiral sulfonated 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,whereineach phenyl group of the sulfonated binaphthyl is monosulfonated, andwherein the decree to which the sulfonated binaphthyl is sulfonated isselected from the group consisting of tetrasulfonated, pentasulfonated,and hexasulfonated.
 15. A method according to claim 14 wherein the metalis selected from the group consisting of rhodium, ruthenium, iridium,vanadium, lead, platinum, tin, nickel and palladium.
 16. A methodaccording to claim 14 wherein the 2-arylacrylic acid is dehydronaproxen.17. A method according to claim 14 wherein the the catalyst furthercomprises a counterion selected from the group consisting of Na⁺, K⁺,Cs⁺ and Ca²⁺.